Safety of Atezolizumab-Bevacizumab in Liver Transplanted Patients With Advanced Hepatocellular Carcinoma

Inclusion Criteria:

* All patients over 18 and under 90 years old:
* who underwent LT more than 6 months ago (to prevent the higher risk of ACR which exists within the first months after LT and to deal with populations with a lowered immunosuppressive regimen long after LT)
* with HCC recurrence diagnosis according to the EASL diagnostic criteria (33)
* with advanced HCC not accessible to surgery and locoregional treatment
* with at least one measurable untreated lesion
* With a proposal for Atezo-Beva in first line treatment made in a multidisciplinary meeting
* Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment, unless otherwise specified:

  * ANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support
  * Lymphocyte count ≥ 0.5 x 109/L (500/µL)
  * Platelet count ≥ 75 x 109/L (75,000/µL) without transfusion
  * Hemoglobin ≥ 90 g/L (9 g/dL). Patients may be transfused to meet this criterion.
  * AST, ALT ≤ 5 x upper limit of normal (ULN)
  * Serum bilirubin ≤ 3x ULN
  * creatinine clearance≥40 mL/min (calculated using the Cockcroft-Gault formula)
  * For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 2x ULN
  * Urine dipstick for proteinuria \< 2+ (within 7 days prior to initiation of study treatment). Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate \<1 g of protein in 24 hours
* ECOG Performance Status of 0 or 1
* For women of childbearing potential and men: agreement to remain abstinent or use effective contraception during treatment and at least :

  * 5 months after the end of the treatment with atezolizumab,
  * 6 months after the end of the treatment with bevacizumab
* Child-Pugh class A

Exclusion Criteria:

* History of ACR within 3 months before starting Atezo-Beva treatment
* Banff score for ACR ≥ 3 on liver biopsy performed before the initiation of the treatment
* Pregnant or breastfeeding woman
* Patient not affiliated to a beneficiary or entitled social security scheme or to the PUMA
* Patient not having signed consent
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT-scan
* History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
* Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
* A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment.
* Inadequately controlled arterial hypertension (defined as systolic blood pressure (BP) ≥ 160 mmHg and/or diastolic blood pressure \> 100 mmHg), based on an average of ≥ 3 BP readings on ≥ 2 sessions Anti-hypertensive therapy to achieve these parameters is allowable.
* Prior history of hypertensive crisis or hypertensive encephalopathy
* History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration
* Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
* Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
* Hypersensitivity to the active substance or to any of the excipients of the SmPC of bevacizumab and the SmPC of atezolizumab
* Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
* Prior arterial thromboembolic reactions including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions;
* Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
* In case of proteinuria \> 1g in 24 hours
* History of leptomeningeal disease
* Active tuberculosis
* Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia